ABSTRACT Understanding the transcriptional programs governing cell identity and function is key to many outstanding questions in biology and biomedicine. Most variants associated with common diseases and traits lie in non- coding, regulatory regions of the genome, and to interpret their function, we need to identify the genes they affect and how those are expressed in the different cells of a tissue within individuals, and quantify how their expression varies across individuals. How these mechanisms are regulated during human development remains poorly understood, and most studies to date have relied on human cell lines or model organisms as proxies. GTEx did not profile tissues from postnatal stages of human development. Regulatory elements and gene networks are highly cell type–specific, and may only be active during precise developmental stages, during which they may also contribute to disease susceptibility. Thus, there is a critical need for measuring the transcriptional and regulatory landscape of tissues and cell types during human development. We will serve as the LDACC for the creation of the developmental GTEx (dGTEx) resource. (1) We will work with the BPC to establish a biobank of 30 tissues from each of 120 human postnatal postmortem donors, consented for broad research use and data sharing. (2) We will select 4 tissues of importance for common diseases, and in which there is tissue remodelling during development - brain, gut, lung and heart. We will profile these tissues with multiple single cell assays including snRNA-seq, multiomic RNA/ATAC, and spatial transcriptomics to create deep molecular maps for variant characterization. (3) We will perform baseline molecular profiling of genome sequence and bulk transcriptome for all samples, and integrate the resource with GTEx. We will use these collective data to identify e/sQTLs; create maps of element-gene relationships across tissues; chart differentiation hierarchies within tissues and across age ranges; nominate cell types in which a set of variants manifest; and map cellular and spatial relationships among cells, cellular programs, and tissue features. This project brings together a team with expertise in human genetics, production science (GTEx, ENCODE), computational biology, single cell technologies, and common disease genetics. We will create a data and biospecimen resource for the scientific community that will underpin studies to understand cellular and tissue changes during human development, genome regulation, and common disease variant interpretation.

NARRATIVE Gene expression changes that occur during postnatal development, and how these are regulated by genetic variation and through epigenetic mechanisms, remains largely unknown in humans. As the Laboratory, Data Analysis, and Coordinating Center for the Developmental Genotype-Tissue Expression Project, we will characterize multiple human tissues across developmental stages using single cell and spatial sequencing technologies to map spatiotemporal changes in gene expression across tissues and development. We will integrate these results with RNA sequencing data from ~3,600 tissue samples, from 120 postnatal post-mortem donors, to identify genetic regulatory effects that are specific to development.